Resistance of Cbl-b-/- Teff to Tregs is infectious

The E3 ubiquitin ligase Cbl-b regulates T cell activation, and dysregulation of this protein in both mice and humans has been associated with autoimmunity. Our lab previously proposed resistance to CD4+CD25+ Tregs as one mechanism for the autoimmunity observed in Cbl-b-/- mice. Recently, we confirmed the in vivo resistance of Cbl-b-/- CD4+CD25- T effectors (Teff) to wild type (WT) Tregs using a model of GVHD. Examining the cells ex vivo, we observed a resistance of Cbl-b-/- Teff to suppression of cytokine production. To further characterize this resistance, WT Teff were examined for their ability to be suppressed by Tregs when mixed with Cbl-b-/- Teff in vitro. We found that WT Teff became resistant to Treg-mediated cytokine suppression when co-cultured with Cbl-b-/- Teff. This is the first evidence that resistance to Tregs is “infectious” and can be transmitted to WT Teff. We next determined that in vitro resistance of Cbl-b-/- Teff is only partially reversed by antibodies to IL-2 and IL-4, suggesting that other mechanisms, in addition to increased production of these cytokines, mediate this resistance. The ability of one subpopulation of Teff to induce Treg resistance in another population may have significant implications for mechanisms underlying autoimmune disease. Finally, using Cbl-b-/- Teff to identify mechanisms of infectious resistance may provide important clues in understanding Treg function and in developing novel strategies for treatment of autoimmune disease.